First gene therapy trial for Hunter syndrome opens in Manchester, UK

Hematopoietic cells

UK regulatory authorities have approved the first trial of a gene therapy for young children with Hunter syndrome.

The UK Medicines and Healthcare Products Regulatory Agency (MHRA), Research Ethics Committee (REC), and Health Research Authority (HRA) have all approved the clinical trial application that was submitted by The University of Manchester in August 2022.

In the combined Phase I and II clinical trial, five children under one year of age with the condition also known as mucopolysaccharidosis type II (MPS II) will be treated with autologous hematopoietic stem cell (HSC) gene therapy.

The children will continue to receive enzyme replacement therapy during treatment, but once the gene therapy begins to work, the research team say part of the trial aims to remove the need for weekly enzyme replacement therapy over the child’s lifetime, while the other aim is to safely target the brain disease suffered by these patients.

The drug was developed over eight years by Brian Bigger, Professor of Cell and Gene Therapy at The University of Manchester.

The clinical trial will be led by Professor Rob Wynn, Consultant Paediatric Haematologist at Royal Manchester Children’s Hospital (RMCH), together with Professor Simon Jones, Consultant in Paediatric Inherited Metabolic Disease at Saint Mary’s Hospital, and Professor Bigger.

Next generation stem cell gene therapy

Children with Hunter syndrome have a missing gene, meaning they cannot produce an important enzyme called iduronate-2-sulfatase or IDS. The gene therapy works by collecting HSCs from the patient and inserting a working copy of the gene into the HSCs using a lentiviral gene therapy vector.

The modified HSCs are then infused back into the patient to engraft in the bone marrow. Following successful engraftment of modified HSCs in the bone marrow, these cells start to produce daughter blood cells which contain the IDS gene and enzyme which are distributed throughout the body, including the brain.

Professor Bigger said: “This is a next generation stem cell gene therapy approach, which allows transit of the IDS enzyme into the brain. The newly inserted IDS gene produces an IDS enzyme that contains a proprietary ApoEII-tagged sequence, which can bind to ApoE-dependent receptors on the blood brain barrier, and move enzyme into the brain more efficiently, thus potentially normalising brain pathology.

“This should speed up delivery of enzyme to the brain, where it is most needed as we can leverage all the enzyme produced by the blood to do this rather than just relying on the engraftment of monocyte cells from the blood into the brain.”

In preclinical studies, mice with Hunter syndrome treated with the HSC gene therapy showed dramatic improvement in their condition, including normalisation of working memory problems, and skeletal features such as the cheekbone dimensions and the width of the humerus and femur bones.

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